Hepatitis C virus (HCV) represents a major health problem for the world. It is a chronic disease that effects mainly the liver and currently there is no cure. Although interferon-alpha and ribavirin are the currently used therapy this approach has many shortcomings. The recent report that the HCV envelope E2 binds to the human CD81 tetraspanin protein has provided valuable new targets for the search for new agents that could block this initial binding of the HCV to human cells. CD81 (TAPA, Target of the Anti-Proliferative Antibody) is a 236-residue protein and a member of the tetraspanin family. The knowledge about CD81 and E2 has stimulated new approach of interfering with the HCV binding to human cells. Our objectives are to: 1- Identify small molecules that will bind to astrocytes containing CD81. Our hypothesis states we will identify new synthetic and natural substances that bind to CD81 and prevent the fusion of HCV with the human cells. Our approach will be to examine libraries of synthetic and natural products obtained in the United States and other countries for their ability to bind to CD81 and a 96 well high throughput assay system. 2- Identify compounds that will bind to the envelop proteins (E1 and E2) and inhibit or interfere with the binding and fusion of the HCV virus to human cells. We will identify compounds that inhibit the spread of a HCV surrogate virus (rVSV, contain envelope proteins, E1 and E2) in cell culture. 3- Model the interaction of CD81 protein and the envelope proteins (E1 and E2) and to show how molecules can interfere with this interaction. Insights gained from this work will aid in the design of new molecules that will be very specific in binding to CD81 or the envelope proteins. The viral attachment and entry in the viral life-cycle has proven to be an effective point to attack with other viruses such as influenza and HIV. Insights gained from modeling and lead compounds should lead to a highly effective treatment and or new methods for the prevention of the HCV infection.